Childhood obesity is a worldwide epidemic which is affecting children at increasingly younger ages. In this project we will compare children with a well-defined genetic origin of obesity with those with obesity of unknown origin to test the hypothesis that obesity itself, independent of genetic mechanism, compromises neural development. Prader-Willi syndrome (PWS) is a contiguous gene defect that results in a well-defined pattern of early-onset childhood obesity. Environmental manipulations (i.e. parental vigilance) can markedly reduce the extent of the obesity in PWS, and potentially protect cognitive function. Therefore, PWS is an excellent model for elucidating the relative contributions of genetics and obesity to brain development. A group of children with early-onset morbid obesity of unknown origin (EMO) will serve as a comparison group to further evaluate our hypothesis that obesity, regardless of the etiology, compromises brain development. Excess adipose tissue results in abnormal levels of a variety of hormones and cytokines. We have recently found that individuals in both these groups (EMO and PWS) had premature development of white matter lesions in the brain, in contrast to their normal weight control siblings (Miller et al, 2006). In this project we will perform qualitative and quantitative measurements of brain MRIs to compare (1) individuals with PWS who become obese early in childhood with (2) individuals with PWS who remain normal weight during early childhood, and (3) children with EMO, and (4) normal weight sibling controls from both groups to test our hypothesis that the abnormal hormonal and metabolic milieu present with early-onset obesity compromises neural development. In this grant we are seeking evidence of a connection between early-onset obesity and brain damage in groups with a different etiology and degree of obesity. This study will provide invaluable information regarding a possible consequence of childhood obesity - damage to the developing brain. Individuals with PWS represent a small fraction of children with early childhood obesity, but will help differentiate the effects of obesity from the effects of genetics, as the group with EMO likely have [sic] a variety of different etiologies for becoming obese. As childhood obesity is an epidemic, the results of this study will have important implications regarding early intervention for children with obesity.